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Investigating the role of brainstem neuroinflammation in cardiorespiratory control in a rat model of recurrent epilepsy

研究脑干神经炎症在复发性癫痫大鼠模型心肺控制中的作用

基本信息

批准号：
10676746
负责人：
Wasif A Osmani
金额：
$ 4.98万
依托单位：
MEDICAL COLLEGE OF WISCONSIN
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10676746
关键词：
Address Affect Animal Model Antiepileptic Agents Apnea Architecture Astrocytes BLR1 gene Baroreflex Bioinformatics Biological Assay Brain Brain Stem Brain region Breathing CCL2 gene CXCL13 gene Cause of Death Cell Nucleus Cells Cessation of life Chemoreceptors Chronic DNA Sequence Alteration Data Epilepsy Event Exons Exposure to Failure Fellowship Female Functional disorder Gene Expression Gene Expression Profile Generations Genes Glial Fibrillary Acidic Protein Goals Health Heart Arrest Heart Rate Hippocampus Human IL1R1 gene Impairment Individual Inflammatory Inpatients Interleukin-1 Intervention Intractable Epilepsy Knock-out Knowledge Lead Life Ligands Mediating Mediator Medical Microglia Modeling Molecular Monitor Morphology Nerve Degeneration Neurologic Neuronal Dysfunction Neurons Nuclear RNA Nucleus solitarius PTGS2 gene Pathologic Pathway Analysis Pathway interactions Patients Pattern Peptide Hydrolases Persons Play Potassium Channel Prevention Proteins Protocols documentation Publishing Rattus Recurrence Respiratory physiology Risk Rodent Model Role Seizures Serotonin Signal Pathway Signal Transduction Small Nuclear RNA System Testing Tissue-Specific Gene Expression Tissues Tonic - clonic seizures audiogenic seizure cell type chemokine chemokine receptor cytokine experience experimental study glial activation high risk human data inward rectifier potassium channel male mortality neural circuit neural network neuroinflammation new therapeutic target novel patient population pharmacologic preBotzinger complex prevent raphe nuclei receptor receptor function respiratory sound sudden unexpected death in epilepsy transcriptome sequencing transcriptomic profiling transcriptomics zinc finger nuclease

项目摘要

Abstract: Epilepsy is one of the most common neurological conditions in the world. Treatment with anti-epileptic drugs (AEDs) prevent recurrent seizures in ~70% of patients with epilepsy, but the remaining 30% of patients with refractory epilepsies continue to experience uncontrolled seizures. The negative consequences of repeated seizures include post-ictal cardiorespiratory suppression putting these patients at high risk of Sudden Unexpected Death in Epilepsy (SUDEP). Fundamental knowledge gaps exist in our understanding of how repeated seizures disrupt the vital cardiorespiratory control systems in the brain. A factor commonly identified in many neurological conditions including epilepsy is neuroinflammation, which supports beneficial functions in health but is dysregulated in epilepsy patients and animal models of seizure disorder. Key cells within the CNS mediating pathological neuroinflammation are resident microglia and astrocytes, which have also been shown to be dysfunctional in human epilepsy. However, it is not known what mechanistic role the glial-derived neuroinflammation plays in the impairment of cardiorespiratory control or increased SUDEP risk. Here, I hypothesize that repeated seizures lead to activation of neuroinflammation mediated by microglia within key brainstem regions controlling cardiorespiratory function causing a progressive decline in these vital functions. Published and preliminary data in our novel rat model with genetic mutations in a gene (kcnj16) encoding an inwardly-rectifying potassium ion channel (Kir5.1; SSkcnj16-/- rats) show that repeated sound-induced seizures (1/day for up to 10 days) lead to progressively more severe post-ictal cardiorespiratory suppression and unexpected mortality particularly in male rats. Through snRNA sequencing and bioinformatic pathway analyses of transcriptomic changes specifically within microglial cells in the medullary raphe (key breathing control region) identified significant predicted activation of IL-1ß signaling following repeated seizures, consistent with immunofluorescent brainstem tissue analyses. Here I propose two Specific Aims which: 1) characterize cell- specific transcriptomic shifts in gene expression within key cardiorespiratory control regions to identify key cells types and pathways mediating local neuroinflammation leading to neuronal dysfunction, and 2) functionally test the roles of microglia and IL-1 signaling in the brain in mediating the progressive cardiorespiratory suppression and/or unexpected seizure-induced mortality. Identifying neuroinflammatory signals/pathways induced by repeated seizures within distinct neural circuits in our novel rat model will enhance our understanding of the pathophysiological consequences of uncontrolled seizures in patients with refractory epilepsy, and hold the potential for identifying new therapeutic targets aimed at preventing seizure-induced cardiorespiratory dysfunction function and reduce SUDEP risk.

摘要：癫痫是世界上最常见的神经系统疾病之一。抗癫痫药物治疗药物 (AED) 可预防约 70% 的癫痫患者复发性癫痫发作，但其余 30% 的患者难治性癫痫患者继续经历不受控制的癫痫发作。重复的负面后果癫痫发作包括发作后心肺抑制，使这些患者面临突发癫痫的高风险癫痫意外死亡 (SUDEP)。我们对如何做到这一点的理解存在基本知识差距反复癫痫发作会破坏大脑中重要的心肺控制系统。通常确定的一个因素是包括癫痫在内的许多神经系统疾病都是神经炎症，它支持神经系统的有益功能但在癫痫患者和癫痫症动物模型中却失调。中枢神经系统内的关键细胞介导病理性神经炎症的是常驻小胶质细胞和星形胶质细胞，这也已被证明在人类癫痫中功能失调。然而，目前尚不清楚胶质细胞来源的机制有何作用。神经炎症会损害心肺控制或增加 SUDEP 风险。在这里，我假设反复癫痫发作导致小胶质细胞介导的神经炎症激活控制心肺功能的关键脑干区域导致这些重要的功能逐渐下降功能。我们的带有基因突变的新型大鼠模型（kcnj16）已发表的初步数据编码内向整流钾离子通道（Kir5.1；SSkcnj16-/- 大鼠）表明，重复的声音诱导癫痫发作（每天 1 次，持续长达 10 天）导致发作后心肺抑制逐渐加重，意外死亡，尤其是雄性大鼠。通过snRNA测序和生物信息通路分析中缝（关键呼吸控制区域）小胶质细胞内的转录组变化确定了反复癫痫发作后 IL-1ß 信号传导的显着激活，与免疫荧光脑干组织分析。在这里，我提出两个具体目标：1）表征细胞- 关键心肺控制区域内基因表达的特定转录组变化，以识别关键细胞介导局部神经炎症导致神经元功能障碍的类型和途径，以及2）功能测试大脑中小胶质细胞和 IL-1 信号传导在介导进行性心肺抑制中的作用和/或意外的癫痫发作引起的死亡。识别由以下因素引起的神经炎症信号/通路在我们的新型大鼠模型中，不同神经回路内的重复癫痫发作将增强我们对难治性癫痫患者癫痫发作失控的病理生理学后果，并坚持确定旨在预防癫痫引起的心肺疾病的新治疗靶点的潜力功能障碍并降低 SUDEP 风险。